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| United States Patent |
5,021,220
|
|
Mertens
|
June 4, 1991
|
Kit for preparing radiodiagnostic examination compositions
Abstract
The invention relates to a method of preparing a chlorinated, brominated,
radiobrominated, iodinated and/or radio-iodinated aromatic or
heteroaromatic compound, in which the (hetero)aromatic nucleus optionally
comprises one or more additional substituents, by reacting the
corresponding halogenated or diazonium-substituted compound in the
presence of a water-soluble acid and of copper ions as a catalyst with a
likewise water-soluble chloride, bromide radiobromide, iodide or
radio-iodide, in which the reaction is carried out in the presence of one
or more reduction agents, which are stable in acid medium, in a quantity
exceeding the quantity of catalyst. The invention also relates to a
composition suitable for diagnostic examination and to a kit for the
preparation thereof. The invention further relates to a method and an
equipment for the preparation of said composition.
| Inventors:
|
Mertens; John (Brussels, BE)
|
| Assignee:
|
Mallinckrodt, Inc. (St. Louis, MO)
|
| Appl. No.:
|
569058 |
| Filed:
|
August 17, 1990 |
Foreign Application Priority Data
| May 24, 1984[BE] | 8491739 |
| Jul 05, 1984[NL] | 8402138 |
| Current U.S. Class: |
424/1.85; 206/569 |
| Intern'l Class: |
A61K 049/02; B65D 069/00 |
| Field of Search: |
424/1.1 APS
206/569
|
References Cited
U.S. Patent Documents
| 4031198 | Jun., 1977 | Jackson et al. | 424/1.
|
| 4032625 | Jun., 1977 | Subramanian et al. | 424/1.
|
| 4942231 | Jul., 1990 | Mertens | 424/1.
|
Primary Examiner: Maples; John S.
Attorney, Agent or Firm: Rothwell, Figg, Ernst & Kurz
Parent Case Text
This is a division of application Ser. No. 417,057, filed Oct. 4, 1989 now
abandoned, which is a continuation of application Ser. No. 735,037 filed
May 17, 1985 now U.S. Pat. No. 4,942,231.
Claims
I claim:
1. A kit for the preparation of a radiodiagnostic examination composition,
comprising a bromine bromine-, or iodine-substituted aromatic or
heteroaromatic starting compound, a water-soluble acid, a copper salt, a
reducing agent stable in an acid medium, and instructions for preparing
the composition by reacting the starting compound with a water-soluble
chloride, bromide radiobromide, iodide or radioiodide in the water-soluble
acid in the presence of (a) the copper salt as a catalyst and (b) the
reducing agent in a quantity exceeding the quantity of the catalyst.
2. A kit according to claim 1 wherein the starting compound comprises a
member of the group consisting of iodophendylate, a 2-, 2,4- or
2,4,6-substituted 1,3,5-triiodobenzene, o-iodohippuric acid or a
pharmaceutically-acceptable salt thereof, iodoamphetamine or a
pharmaceutically-acceptable derivative thereof, iodo-.omega.-phenyl fatty
acid or a pharmaceutically-acceptable salt thereof, and rose bengal.
3. A kit according to claim 1 or 2 wherein the reducing agent is a member
of the group consisting of a pharmaceutically-acceptable Sn(II) salt,
ascorbic acid, isoascorbic acid, citric acid, a monosaccharide, gentisic
acid and pharmaceutically-acceptable salts of said acids.
4. A kit according to claim 1 wherein the starting compound is
o-iodohippuric acid or a pharmaceutically-acceptable salt thereof and the
reducing agent is ascorbic acid.
5. A kit according to claim 1 wherein the instructions include the steps of
(I) reacting the starting compound with a water-soluble iodide or
radioiodide in said acid medium in the presence of (a) copper ions as a
catalyst and (b) said reducing agent, which is stable in said acid medium,
in a quantity exceeding the quantity of the catalyst;
(II) placing the compound obtained in step (I) in a vial closed with a
pierceable stopper;
(III) adding a pharmaceutically-acceptable formulation liquid to the vial;
and
(IV) withdrawing the liquid from the vial through a sterilizing filter and
into an injection syringe.
6. A kit according to claim 1, further comprising:
(a) a supply syringe comprising a barrel, a hollow needle connected to the
barrel and a plunger disposed within the barrel, a side wall of the barrel
comprising an aperture spaced a distance from the needle whereby
formulation liquid within the barrel can be separated from the aperture by
the plunger, but by withdrawing the plunger the formulation liquid can
communicate through the aperture with an atmosphere outside the syringe;
(b) a vial, for accommodating a radiodiagnostic composition, comprising a
pierceable stopper; and
(c) an injection syringe.
Description
Method of preparing a chlorinated, brominated, radiobrominated, iodinated
and/or radioiodinated aromatic or heteroaromatic compound, and kit
therefor.
The invention relates to a method of preparing a chlorinated, brominated,
radiobrominated, iodinated and/or radioiodinated aromatic or
heteroaromatic compound, in which the (hetero)aromatic nucleus optionally
comprises one or more additional substituents, by reacting the
corresponding halogenated or diazonium-substituted compound in the
presence of a water-soluble acid and copper ions as a catalyst with a
likewise water-soluble chloride, bromide, radiobromide, iodide or
radioiodide.
Such aromatic substitution reactions in which, for example, a diazonium
group is substituted by a halogen atom (Sandmeyer reaction) or a halogen
atom is replaced by a different or a radiolabelled halogen atom, are
frequently described in literature. However, in these reactions undesired
by-products are often formed which lead to a contaminated final product.
The reaction also often runs off incompletely, as a result of which the
final product still contains undesired starting material.
This is a serious disadvantage, in particular for the preparation of
substances having a pharmaceutical or diagnostic application for which a
high degree of purity is required. An often elaborate purification process
then is necessary to reach a purity which is acceptable for pharmaceutical
application. This is the more important in preparing compounds for
radiodiagnostic examination, because for these compounds a purification
afterwards may give rise to a considerable reduction of radioactivity due
to natural decay of the radioisotope.
Compounds for radiodiagnostic examination, i.e. radiolabelled compounds,
may be used, for example, for the examination into deviations in shape and
function of internal organs and into the presence and location of
pathological processes in the body. For this purpose, a composition in
which the radiolabelled compound is present can be administered to the
patient, for example, in the form of an injectable liquid. By means of
suitable detection device, for example, a gamma camera, images can be
obtained by observing or recording the emitted radiation, of, for example,
the organ, the body fluid or the pathological process in which the
radiolabelled compound is incorporated.
A radiolabelled compound suitable for this purpose is radioiodinated
o-iodohippuric acid or a salt thereof. This radiolabelled compound has
been found to be particularly suitable for examining the renal function.
The readily available sodium salt of o-iodohippuric acid, labelled with
iodine-131, is often used for this purpose. Because the radiation
characteristics of iodine-131 are less favourable and the half-life of
said radioisotope is comparatively long for use in radiodiagnostics for
examining the renal function, it has more recently been suggested to use
iodine-123 labelled o-iodohippuric acid or a salt thereof. Iodine-123 has
a comparatively short half-life, namely approximately 13 hours, as a
result of which compounds of this radioisotope are on the one hand very
suitable, for example, for examining the renal function but on the other
hand may present logistic problems after the iostope has been produced in
a cyclotron. Hawkins et al. described in Eur. J. Nucl. Med. 1982, 7, pp.
58-61 a fast method of preparing iodine-123-o-iodohippuric acid. In view
of the above-mentioned logistic problems of iodine-123 labelled compounds,
the said authors have suggested a kit preparation method in which the user
himself, i.e. the clinic or the clinical laboratory, can prepare the
radiolabelled compound by using a so-called kit. This kit comprises all
the constituents which are necessary for the preparation, and usually
instructions for use. A kit described by Hawkins et al. comprises the
following constituents: acetate buffer, o-iodohippuric acid in 50%
ethanol, an aqueous solution of copper sulphate and an aqueous solution of
iodine-123 labelled sodium iodide. The combined ingredients were heated in
an autoclave for 15 minutes at 121.degree. C., producing the desired
iodine-123-o-iodohippuric acid in a yield of 94%; 5% free iodine-123 was
still present. The same result could be obtained by using a kit in a
freeze-dried form in which a phosphate buffer was preferred to an acetate
buffer.
The disadvantage of the above-described method is the still incomplete
conversion to the desired radiolabelled compound. When used as a
radiodiagnostic, the remaining free iodine-123 does not take part in the
intended examination, but goes entirely to the thyroid gland which is thus
burdened unnecessarily.
It has also been found that the use of an oxidant, for example manganic
oxide, potassium permanganate or potassium iodate, instead of copper ions,
does not result in a complete conversion. Upon radioiodinating rose bengal
with iodine-131 in the presence of an oxidant, as described in U.S. Pat.
No. 4,298,591, a conversion higher than approximately 90% could not be
achieved.
Apparently, the preparation of radioiodinated amphetamine and derivatives
thereof also presents great problems, as appears from European Patent No.
11858. After a technically unattractive preparation method in ethanol as a
solvent in a closed tube at 121.degree. C., the resulting product must be
subjected to several purification steps.
Mills has described in Int. J. Appl. Rad. Isot., Vol. 33, 1982, pp.
467-468, the radioiodination of diatrizoic acid by reacting iodine-123
labelled sodiumiodide with diatrizoic acid in the presence of copper
sulphate at a pH between 3 and 4. As will appear from the Examples, under
the reaction conditions described by Mills, viz. heating for 15 minutes at
125.degree. C., the desired radiolabelled product could be obtained in an
average yield of only 82%. So also in this case the conversion is rather
incomplete and the reaction temperature required, viz. 125.degree. C., is
unfavourable for kit purposes (see further).
It is the object of the present invention to provide a method for the
preparation described in the opening paragraph which does not present the
above-mentioned disadvantages and in which the desired product is produced
in a high yield without interfering starting materials or by-products
being present.
According to the invention this object can be achieved by performing the
substitution reaction mentioned in the opening paragraph in the presence
of one or more reduction agents, which are stable in acid medium, in a
quantity exceeding the quantity of the catalyst used. It has been found
surprisingly that as a result of this the yield of the product formed in
the substitution reaction can be considerably increased, even up to
approximately 100% in the preparation of e.g. radioiodinated
o-iodohippuric acid, amphetamine derivatives, iodinated thyrosine,
diatrizoic acid, iodinated benzylguanidine, and iodinated
benzylpropanediamine derivatives.
The invention relates more in particular to the preparation of a
brominated, radiobrominated, iodinated or radioiodinated aromatic or
heteroaromatic compound, in which the (hetero)aromatic nucleus is a
benzene nucleus, a naphthalene nucleus, a pyridine nucleus, a pyrimidine
nucleus, a quinoline nucleus or an indole nucleus which comprises one or
more additional substituents. Although the invention is particularly
suitable for the preparation of radiolabelled compounds from the
corresponding non-labelled compounds, the invention is by no means
restricted thereto. (Hetero)aromatic compounds substituted with chlorine
or non-labelled bromine or iodine can also be prepared from the
corresponding halogen compounds or diazonium compounds by using the method
according to the invention. Suitable non-radiolabelled iodine compounds
which can be prepared by using the method according to the invention are
iodine-containing contrast media, for example iophendylate and other ones
on the basis of 2-, 2,4- or 2,4,6-substituted 1,3,5-triiodobenzene, for
example, acetrizoic acid, adipiodone, amidotrizoic acid or diatrizoic
acid, bunamiodyl, phenobutiodil, iobenzamic acid, iocarmic acid, iocetamic
acid, iodamide, iodoxamic acid, ioglycamic acid, iopanoic acid, iopodic
acid, iothalamic acid, ioxithalamic acid, metrizamide, metrizoic acid,
tyropanic acid, and salts of the above-mentioned acids. Other suitable,
non-radiolabelled compounds which can be prepared according to the
invention from the corresponding halogen compounds of diazonium compounds
are starting substances for radioiodinated diagnostics, for example,
o-iodohippuric acid or salts thereof, iodoamphetamine or derivatives
thereof, iodo-.omega.-phenyl fatty acids or salts thereof and rose bengal.
As stated hereinbefore, the invention is excellently suitable for the
preparation of radiolabelled bromine or radiolabelled iodine compounds by
reacting the corresponding non-radiolabelled bromine or iodine compounds
in acid medium in the presence of a reduction agent with a water-soluble
radiolabelled bromide or iodide. As a water-soluble bromide or iodide is
preferably chosen an alkali metal bromide or iodide, for example, a sodium
bromide or iodide or a potassium bromide or iodide. Radioisotopes suitable
for this purpose are bromine-77, iodine-123, iodine-125 and iodine-131; as
described hereinbefore, the best suitable of these iodine isotopes for use
in radio-diagnostic compounds is iodine-123. Therefore, a iodine-123
labelled sodium iodide solution or potassium iodide-solution is preferably
chosen for the substitution reaction. Various radioiodinated important
diagnostics can simply and in a high yield be prepared in this manner, for
example, radioiodinated o-hippuric acid and salts thereof, labelled
iodoamphetamine and derivatives thereof, labelled iodo-.omega.-phenyl
fatty acids and salts thereof, labelled iodinated thyrosines, such as
labelled mono-, di-, tri- and tetraiodothyrosine, labelled
1,3,5-triiodobenzene derivatives, such as labelled diatrizoic acid and
salts thereof, labelled halogenated benzylguanidine, such as
m-iodobenzylguanidine, and labelled
N,N,N'-trimethyl-N'-(2-hydroxy-3-methyl-5-iodobenzyl)-1,3-propanediamine.
Labelled iodoamphetamine derivatives important for diagnostic purposes are
labelled N-lower alkyl-substituted iodoamphetamines, for example,
N-isopropyl-iodoamphetamine. Other interesting halogen-containing
compounds which may be radioiodinated according to the invention are: rose
bengal, N-iodoquinolyn-N,N'-dimethylpropanediamine, p-iodosulphonamide,
N-iodophenylsulphonyl-N'-ethylurea, glibenclamed,
3-iodo-4-aminophenylethylamine, N,N-dimethyliodobenzylamine, substituted
or non-substituted iodopyridines or iodopyridine-oxides, mono- and
triiodobenzoic acid,
N-[3-acetyl-4-(3-isopropylamino-2-hydroxy)propoxyphenyl]-iodobenzamide,
iodinated indocyanine green, iodinated hydroxybenzylpindolol, iodinated
thiouracil, iodinated estradiol, halogenated phenothiazines, halogenated
benzodiazepines, halogenated metyrapone, halogenated butyrophenone
derivatives, halogenated dibenzazepines, halogenated thyroid gland
hormones as mentioned before, iodoantipyrine, and iodine-containing
contrast media, for example iophendylate and other ones on the basis of
2-, 2,4-, and 2,4,6-substituted 1,3,5-triiodobenzene.
Reduction agents which are very suitable for use in the method according to
the invention are Sn(II) salts. In addition to Sn(II) salts are preferably
used one or more antioxidants, for example, metallic tin, ascorbic acid,
citric acid, a monosaccharide or gentisic acid. Of these antioxidants
ascorbic acid has been found to be particularly suitable for use together
with a Sn(II) salt; when ascorbic acid is used, this acid may in addition
have the function of water-soluble acid.
In addition to Sn(II) salts, other reduction agents stable in acid medium
may successfully be used, for example, ascorbic acid, isoascorbic acid,
citric acid, a monosaccharide, or a sulphite. The use of ascorbic acid as
a reduction agent is to be preferred due to its extremely favourable
influence on the desired substitution reaction, the ready availability and
the suitability to use it in pharmaceutical compositions; moreover,
ascorbic acid may serve as the water-soluble acid required for the
reaction.
For example, radioiodinated o-iodo-hippuric acid or salts thereof,
iodoamphetamine or derivatives thereof, iodo-phenyl fatty acids or salts
thereof, iodobenzylguanidine, iodobenzylpropanediamine derivatives, and
iodothyrosines can be prepared substantially quantitatively by reacting
the corresponding non-radioactive bromine- or iodine-substituted compounds
in the presence of a water-soluble acid and of copper ions as a catalyst
with likewise water-soluble radioactive iodide, provided the reaction is
carried out in the presence of ascorbic acid as a reduction agent.
Indeed, it has been found that in the preparation of radioiodinated
o-iodohippuric acid or salts thereof, the catalyst may even be absent to
still get a substantially quantititative result of the desired reaction.
It is therefore to be considered a particular aspect of the invention that
radioiodinated o-iodohuppuric acid or salts thereof can successfully be
prepared by a simple reaction of the corresponding compound substituted
with non-radioactive bromine or iodine with a water-soluble radioactive
iodide in the presence of ascorbic acid as a reduction agent.
The reaction according to the invention can be readily carried out in an
aqueous solution which comprises, if so desired, salts and one or more
water-miscible organic solvents, for example, ethanol, methanol or
acetone. Organic solvents as well as other auxiliary substances to improve
the solubility have the disadvantage, however, of being potentially toxic.
It is of great advantage that the reaction mixture can be directly
introduced as a pharmaceutical composition in the blood stream of the
living being without any further purification - for example,
distilling-off organic solvent. In the reaction described by Hawkins et al
in Eur. J. Nucl. Med. 1982, 7, 58-61 and in European patent 11858 a
considerable quantity of ethanol is used, as a result of which the
resulting reaction mixture is less suitable to be used as such as a
radiodiagnostic. A particular advantage of the reaction according to the
invention is that it gives a substantially quantitative result in a
solution which is entirely free or substantially entirely free from
organic solvent. The resulting reaction mixture can therefore be used
directly for pharmaceutical applications by administering it, for example,
intravenously or subcutaneously to a living being. The reaction is
therefore preferably carried out in a sterile solution having a pH
suitable for physiological application.
It is an extra aspect of the invention that the reaction can be carried out
at a temperature which is suitable for use in a clinic or a clinical
laboratory. This is important in particular for the preparation of
compounds labelled with radioactive bromine or iodine. These compounds,
having a comparatively short life in connection with natural decay of the
radioisotope used, can then be prepared in situ by the user and be used
immediately thereafter. It has been found that the desired substitution
reaction proceeds excellently at a temperature of approximately
121.degree. C., a temperature at which compositions for intravenous or
subcutaneous administration have to be sterilized. Although some clinics
or clinical laboratories have the disposal of an autoclave with which
sterilizations at 121.degree. C. can be carried out, this is not the
general rule. A preparation on or in a water bath, however, can simply be
realized in any clinic and any clinical laboratory. It is therefore of
particular importance that the reaction according to the invention has
been found to result in the desired product quanititatively already at
approximately 100.degree. C. This is another great advantage as compared
with the methods described by Hawkins et al. and by Mills, in which
temperatures of 121.degree. C. and 125.degree. C. respectively were
necessary for conversions to only 94% and 82% respectively.
The invention also relates to a composition suitable for diagnostic
examination which comprises, in addition to a pharmaceutically acceptable
formulation liquid and/or one or more auxiliary substances, a
iodine-containing contrast medium which has been prepared by using the
method according to the invention, and to a composition which is suitable
for diagnostic examination, which comprises a radioiodinated diagnostic,
and which has also been prepared by using the method according to the
invention.
The invention further relates to a method of preparing the above injectable
composition. This method is carried out in that a pharmaceutically
acceptable formulation liquid, which may comprise one or more auxiliary
substances and is accomodated in at least one supply syringe, is added to
the radioiodinated diagnostic, which radiodiagnostic containing substance
is accomodated in a vial, sealingly closed with a pierceable stopper, said
addition being carried out by piercing the stopper of said vial with the
needle or needles of said supply syringe or syringes, and by then allowing
the formulation liquid in said supply syringe or syringes to communicate
with the atmospheric pressure to enable said liquid to reach the substance
in the vial through the needle or needles, and that the composition in the
vial thus obtained is then transferred to an injection syringe by piercing
the stopper of said vial with the needle of said injection syringe and by
then sucking the composition into the injection syringe, during which
addition and/or transfer said formulation liquid and/or injectable
composition preferably flow(s) through at least one sterilizing filter.
If said addition and transfer are carried out in a sterile atmosphere, e.g.
under laminar flow conditions, sterilizing filters may be omitted.
BRIEF DESCRIPTION OF THE FIGURE
The sole FIGURE is a new elevational view partially schematic with portions
broken away and in partial cross-section, of equipment forming a kit in
accordance with the present invention.
The invention also relates to an equipment for carrying out the above
method, which equipment comprises
(a) at least one supply syringe, provided with a cylindrical barrel for
accomodating a formulation liquid, to which barrel a hollow needle is
sealingly connected and in which barrel a plunger is movably positioned,
the cylindrical side-wall of said barrel being provided with at least one
aperture in such distance from the attached needle, that the formulation
liquid to be accomodated in the barrel can be separated from the aperture
in the barrel wall by means of the plunger, but that by withdrawing the
plunger said aperture can allow said formulation liquid to communicate
with the atmospheric pressure outside the syringe,
(b) a vial for accomodating a radiodiagnostic containing substance, which
vial is sealingly closed with a pierceable stopper, and
(c) an injection syringe, provided with a cylindrical barrel for
accomodating an injectable composition, to which barrel a hollow needle is
sealingly connected, if desired, through an intermediately positioned
sterilizing filter means, the needle having a length sufficient for
reaching the bottom of the vial after having pierced the stopper of said
vial, and in which barrel a plunger is movably positioned.
Moreover the invention relates to the above-defined syringe for said
equipment, provided with a cylindrical barrel for accomodating a
formulation liquid.
The invention further relates to a method of radio-assaying a warmblooded
living being, in particular a human being, by administering the above
radiodiagnostic composition to the being, in which the quantity of
radioactivity administered should be sufficient for detection by external
imaging. The being is then subjected to external imagining, for example
with a gamma camera, to detect the accumulated radioactivity and thus to
determine the location thereof in the body, or to establish the function
of an organ. A quantity of radioactive material to be administered which
is sufficient for detection by external imaging is approximately 0.1 to
approximately 10 millicurie per 70 kg of bodyweight; the radioactive
material is preferably administered in a quantity of 0.1 to 7 millicurie
per 70 kg of body weight.
As described hereinbefore, the reaction according to the invention for the
preparation of radioactive compounds is excellently suitable for a kit
preparation. This means that a so-called "cold" kit in which all the
ingredients for the preparation reaction are present with the exception of
the radioactive iodide or bromide, is placed available to the user. The
radioactive material is placed to the user's disposal separately. The user
himself can now perform the reaction according to the invention by taking
the kit destined for preparing the radiolabelled compound which he desires
and mixing the ingredients thereof with the radiolabelled iodide or
bromide, by heating the resulting mixture for a short period of time, for
example at 100.degree. C., a composition suitable for diagnostic
examination is obtained. If desired, a formulation liquid may be added to
the mixture prior to or after heating. The ingredients are preferably
present in the kit in a freeze-dried form; this is in favour of the
stability.
It will be obvious from the above that the invention relates also and in
particular to a kit for preparing a composition suitable for
radiodiagnostic examination. In addition to the bromine-substituted or
iodine-substituted aromatic or heteroaromatic compound in which the
(hetero)-aromatic nucleus optionally comprises one or more additional
substituents, to a water-soluble acid, a copper salt and, if desired, a
pharmaceutically acceptable formulation liquid and/or auxiliary
substances, the said kit comprises a reduction agent as described
hereinbefore. The kit furthermore comprises instructions for use with a
prescription for carrying out the method.
Finally, the invention also relates to a kit for preparing radioiodinated
o-iodohippuric acid or a salt thereof, comprising the non-labelled
compound, if desired a pharmaceutically acceptable formulation liquid
and/or auxiliary substances, and ascorbic acid as a reduction agent. This
kit also comprises instructions for use.
The invention will now be described in greater detail with reference to the
ensuing specific examples.
EXAMPLE I
3.3 .mu.mol Cu(II) (solution of 32.5 mg of CuSO.sub.4.5H.sub.2 O per 10 ml
of water), 43 .mu.mol of ascorbic acid, 0.3 .mu.mol of
N-isopropyl-para-iodoamphetamine.HCl, 30 .mu.l of a iodine-123 labelled
sodium iodide solution having a specific activity of 0.5 mCi/.mu.l and 150
.mu.l of water were heated, after mixing, in a closed vial at 100.degree.
C. for 30 minutes. The resulting labelling efficiency of the radiolabelled
product was determined by radio-HPLC and was higher than 99%, while no
radioactive by-products could be detected. Nor could non-labelled
by-products be detected by means of UV-spectroscopy.
The same results were obtained when in addition 0.4 .mu.mol of Sn(II) were
added.
EXAMPLE II
50 .mu.l of Cu(NO.sub.3).sub.2 in an acetic acid (96%) solution (1.3
mg/ml), 1 mg of SnCl.sub.2.2H.sub.2 O and 1 mg of
N-isopropyl-para-iodoamphetamine.HCl were mixed in a closed reaction vial.
A chip of metallic tin and 20 .mu.l of iodine-123 containing sodium iodide
solution (specific activity 0.5 mCi/.mu.l) were then added. The vial was
then heated to 170.degree. C. for 30 minutes. The resulting labelling
efficiency, determined by radio-HPLC, was higher than 99%. The reaction
product thus obtained was then brought at pH 10 to 11 with a 1 molar NaOH
solution and chromatographed over a micro column with Prep.Bondapack C18
(55-105.mu.; reg. trademark) packing. The column was then rinsed with 10
ml of H.sub.2 O and the N-isopropyl-p-I-amphetamine was eluted
quantitatively with 2-3 ml of acidified ethanol.
When instead of iodine-123 sodium iodide a bromine-77 containing sodium
bromide solution was used, the radiobromine-labelled amphetamine
derivative could be prepared under substantially the same conditions.
Iodine-123 labelled N-isopropyl-para-iodoamphetamine could also be obtained
by starting from N-isopropyl-para-bromoaphetamine, by reacting it with
iodine-123 labelled sodium iodide.
EXAMPLE III
0.2 mg of ortho-iodohippuric acid, 2 mg ascorbic acid, 1-3 .mu.mol
CuSO.sub.4, 0.5 ml H.sub.2 O and radioactive iodide (50 .mu.l of a sodium
iodide solution labelled with iodine-123; activity 25 mCi) were mixed in a
closed vial and heated at substantially 100.degree. C. for 5 minutes.
By means of radio-HPLC it was demonstrated that the labelling efficiency
was substantially 100%, while no radioactive or non-labelled by-products
could be detected (UV).
The reaction has been carried out with the same result using a iodine-131
labelled sodium iodide solution.
EXAMPLE IV
1 mg of p-bromophenylhexadecane carboxylic acid, 0.3 ml MeOH/H.sub.2 O
(90/10), 2 .mu.mol CuSO.sub.4, 4 mg of ascorbic acid and 50 .mu.l of a
iodine-123 labelled sodium iodide solution (activity 25 mCi) were heated
at 150.degree. C. in a closed reaction vessel for 1 hour.
The desired iodine-123 labelled product was obtained in a labelling
efficiency of more than 90%, while substantially no by-products were
formed.
EXAMPLE V
1 mg of p-iodophenylhexadecane carboxylic acid, 0.3 ml of MeOH/H.sub.2
O(90/10), 2 .mu.mol CuSO.sub.4, 4 mg of ascorbic acid and 5 .mu.l of a
iodine-123 labelled sodium iodide solution (activity 2.5 mCi) were heated
at 100.degree. C. in a closed reaction vial for 30 minutes. The labelling
efficiency was substantially 100%; this was determined by means of
radio-HPLC.
EXAMPLE VI
Kit preparation for an injectable radioiodinated
N-isopropyl-p-iodoamphetamine solution, as well as the use of said
solution.
The following components were added together in the given sequence:
(1) 2 mg of N-isopropyl-p-iodoamphetamine.HCl (5.9 .mu.-mol),
(2) 10 mg of ascorbic acid
(3) 460 .mu.l of water,
(4) 40 .mu.l of CuSO.sub.4 solution (5.2 .mu.mol), and
(5) 10 .mu.l of SnSO.sub.4 solution (0.44 .mu.mol).
After freeze-drying, the mixture was added under nitrogen to a sterile
closed vial, after which 0.5 ml of sterile oxygen-free water and 10 .mu.l
iodine-123 labelled sodium iodide solution were successively added (5
mCi). The vial was heated at 100.degree. C. for 30 minutes. In order to
obtain an isotonic solution having a pH of approximately 6 suitable for
injection, 1.5 ml of a sterile aqueous solution containing per millilitre
6 mg of NaCl. 3.3 mg of ascorbic acid and 2.42 mg of Na.sub.2
CO.sub.3.10H.sub.2 O were added to the resulting reaction mixture.
The labelling efficiency of the resulting composition was determined by
means of radio-HPLC and was over 99%. Non-labelled by-products could not
be detected (UV). When no sterile solutions were used, the composition was
sterilized afterwards by filtration over a 0.22.mu. filter; the
composition then did not differ from the above one.
The sterilized composition was administered intravenously to a patient in a
quantity of 2.5 mCi. Excellent scintigraphic images of the brains were
obtained by means of a gamma camera.
EXAMPLE VII
Preparation of radioiodinated o-iodohippuric acid and kit for a composition
provided with the said radiodiagnostic.
1 ml of sterile oxygen-free water and 20 .mu.l of a sterile iodine-123
labelled sodium iodide solution were added successively to 1 mg of
o-iodohippuric acid sodium salt and 4 mg of ascorbic acid in a sterile
closed vial under nitrogen (total activity 10 mCi). The vial was heated at
100.degree. C. for 10 minutes. The labelling efficiency was determined by
means of radio-HPLC and was approximately 100%. Labelled or
non-radioactive by-products were not detected. In order to obtain an
isotonic solution having a pH suitable for injection, 1 ml of a sterile
aqueous solution was added comprising 4 mg of ascorbic acid, 14 mg of NaCl
and 5 mg of Na.sub.2 CO.sub.3.10H.sub.2 O.
When no sterile solutions were used, the resulting compositions was
sterilized afterwards as described in Example VI.
When a iodine-131 labelled sodium iodide solution was used, the iodine-131
labelled o-iodohippuric acid was obtained with the same labelling
efficiency.
EXAMPLE VIII
Kit preparation for an injectable radioiodinated
N-isopropyl-p-iodoamphetamine (IAMP) solution, as well as the use of said
solution.
The following components were added together in the given sequence:
(1) 2 mg of pure N-isopropyl-p-iodoamphetamine sulphate
(2) 10 mg of L-ascorbic acid
(3) 5 mg of gentisic acid
(4) 1 mg of SnSO.sub.4
(5) 4.5 mg of sodium citrate.2H.sub.2 O
(6) 1.2 mg of Na.sub.2 SO.sub.4
(7) 1000 .mu.l of oxygen-free water
(8) 40 .mu.l of CuSO.sub.4 solution (32.5 mg CuSO.sub.4.5H.sub.2 O/10 ml
H.sub.2 O).
The mixture was added through a 0.22.mu. sterilizing filter to a sterile
and apyrogen vial, then freeze-dried in a sterile nitrogen atmosphere and
septum-closed under these conditions.
For clinical preparation 1 ml of sterile oxygen-free water and 5 .mu.l of
sterile iodine-123 labelled sodium iodide solution (2 mCi) or 1 ml of
sterile iodine-123 labelled sodium iodide solution (containing the
required activity) were added. The septum-closed vial was heated at
100.degree. C. for 30 minutes.
The obtained solution was isotonic and of injectable pH. The labelling
efficiency of the resulting composition, as determined by means of
radio-HPLC, was over 99% (average of 20 experiments). Non-labelled
by-products could not be detected (UV detection).
The composition was administered intravenously to a patient in a quantity
of 2 to 4 mCi. Excellent scintigraphic images of the brains were obtained
with both a planar (2 mCi) and SPECT (4 mCi) .gamma.-camera.
The composition was found stable for at least 24 hours. Use of the
.sup.123- I-solution in amounts varying from 5 to 50 .mu.l (5 to 25 mCi)
yielded equal results.
EXAMPLE IX
Kit preparation for an injectable radioiodinated o-iodo-hippuric acid
solution, as well as the use of said solution.
2 mg of pure o-iodo-hippuric acid
5 mg of gentisic acid
10 mg of L-ascorbic acid
1 mg of SnSO.sub.4
1000 .mu.l of oxygen-free water
1 .mu.l of a CuSO.sub.4 solution (300 .mu.g CuSO.sub.4.5H.sub.2 O/10 ml)
The above mixture was treated and freeze-dried as mentioned in Example
VIII.
The clinical preparation was carried out in two steps:
(1) 1 ml of sterile oxygen-free water and 2.5 .mu.l of sterile .sup.123-
I-solution (1 mCi) or 1 ml of a sterile .sup.123- I-solution (containing
the required activity) were added. The septum-closed vial was heated at
100.degree. C. for 20 minutes.
(2) 1 ml of a sterile oxygen-free aqueous solution containing 12 mg of
sodium citrate and 23 mg of Na.sub.2 SO.sub.4 /ml were added to the
reaction mixture to obtain a sterile isotonic solution of injectable pH. A
labelling of 99% has been obtained. HPLC control showed neither labelled
nor unlabelled side products. The composition was stable for at least 24
hours.
The composition administrated was used with success for non invasive kidney
studies (1 mCi intravenously injected).
Use of the .sup.123- I-solution in amounts varying from 2.5 to 50 .mu.l (1
to 20 mCi) yielded equal results.
EXAMPLE X
Kit preparation for an injectable radioiodinated m-iodobenzylguanidine
(MIBG) solution as well as the use of said solution.
The following components were added together in the given sequence:
(1) 2 mg of pure m-iodobenzylguanidine sulphate
(2) 10 mg of L-ascorbic acid
(3) 5 mg of citric acid
(4) 0.5 mg of SnSO.sub.4
(5) 500 .mu.l of oxygen-free water
(6) 10 .mu.l of CuSO.sub.4 solution (32.5 mg CuSO.sub.4.5H.sub.2 O/10 ml
H.sub.2 O).
The above mixture was treated and freeze-dried as described in example
VIII.
The clinical preparation was carried out in two steps:
1) 500 .mu.l of sterile oxygen-free water and 10 .mu.l of sterile .sup.123-
I-solution (4 mCi) or 1 ml of a sterile .sup.123- I-solution (containing
the required activity) were added. The septum-closed vial was heated at
100.degree. C. for 20 minutes.
2) 1.5 ml of a sterile oxygen-free aqueous solution containing 5 mg of
sodium citrate and 30 mg of Na.sub.2 SO.sub.4 /1.5 ml water were added to
the reaction mixture to obtain a sterile isotonic solution of injectable
pH. A labelling yield of >99% has been obtained. HPLC control did not show
any labelled or unlabelled by-products. The composition was stable for at
least 15 hours.
The composition administered intravenously (4 mCi per 70 kg body weight)
was used with success for the .gamma.-scintigraphic diagnosis of
neuroblastoma and phenochromocytoma. Use of the .sup.123- I-solution in
amounts varying from 10 to 50 .mu.l (4 to 20 mCi) yielded equal results.
The above-described labelling conditions and clinical preparation also
yielded pure .sup.131 I-MIBG (>99% labelling yield) at a dose of 2 mCi
.sup.131 I.
EXAMPLE XI
Kit preparation for an injectable radioiodinated p-iodophenyl-pentadecanoic
acid (PIPPA) solution.
The following components were added together in a 3 ml vial in nitrogen
atmosphere.
0.4 mg of p-iodophenylpentadecanoic acid
0.6 mg of SnSO.sub.4
2.3 mg of L-ascorbic acid
50 .mu.l of oxygen-free water
10 .mu.l of CuSO.sub.4 solution (32.5 mg CuSO.sub.4.5H.sub.2 O/10 ml)
100 .mu.l ethanol
5 .mu.l iodine-123 labelled sodium iodide solution (2 mCi)
The septum-closed vial was heated at 100.degree. C. during 30 minutes. A
labelling yield of 98.5% was obtained. After cooling down the solution was
made up with 1.8 ml of a 6% Human serum albumine solution and sterilised
through a 0.22.mu. filter and recovered in a sterile and pyrogenfree vial
filled with nitrogen gas.
Use of the .sup.123- I-solution in amounts varying from 5 to 50 .mu.l (2 to
25 mCi) yielded equal results.
EXAMPLE XII
Kit preparation for an injectable radioiodinated
N,N,N'-trimethyl-N'-(2-hydroxy-3-methyl-5-iodobenzyl)-1,3-propanediamine
(HIPDM) solution, as well as the use of said solution.
The following components were added together in the given sequence:
1) 2 mg of pure
N,N,N'-trimethyl-N'-(2-hydroxy-3-methyl-5-iodobenzyl)-1,3-propanediamine
2) 10 mg of L-ascorbic acid
3) 5 mg of gentisic acid
4) 1 mg of SnSO.sub.4
5) 4.5 mg of sodium citrate.2H.sub.2 O
6) 1.2 mg of sodium sulphate
7) 1000 .mu.l of oxygen-free water
8) 40 .mu.l of CuSO.sub.4 solution (32.5 mg CuSO.sub.4.5H.sub.2 O/10 ml
H.sub.2 O
The above mixture was added through a 0.22.mu. sterilizing filter to a
sterile and pyrogenfree vial and was freeze-dried in a sterile nitrogen
atmosphere and septum-closed under these conditions. For clinical
preparation 1 ml of sterile oxygen-free water and 5 .mu.l of sterile
iodine 123-labelled sodium iodide solution (2 mCi) or 1 ml of sterile
iodine-123 labelled sodium iodide solution (containing the required
activity) were added. The septum-closed vial was heated at 100.degree. C.
for 30 minutes. The obtained solution is isotonic and of injectable pH. A
labelling yield of 99% has been obtained. Neither labelled nor unlabelled
side products have been observed.
The composition is administered intravenously to a patient (2 to 5 mCi
amounts) for brainscintigraphy. Use of the .sup.123- I-solution in amounts
varying from 5 to 50 .mu.l (2-25 mCi) yielded equal results.
EXAMPLE XIII
Radioiodination of mono-iodothyrosine
The following components were added together in the given sequence:
1) 0.3 mg of pure mono-iodothyrosine
2) 10 mg of L-ascorbic acid
3) 230 .mu.l of oxygen-free water
4) 70 .mu.l of CuSO.sub.4 solution (32.5 mg CuSO.sub.4.5H.sub.2 O/10 ml)
(5) radioiodide solution in amounts varying from 5 to 50 .mu.l
The above mixture was heated in a septum-closed vial during 2 minutes at
100.degree. C. A labelling yield of more than 99% was obtained. After 10
minutes of heating no side-products could be observed.
EXAMPLE XIV
Radioiodination of di-iodothyrosine
0.3 mg of di-iodothyrosine was labelled under identical conditions as
described for mono-iodothyrosine (example XIII). A labelling yield of at
least 99% was obtained within 2 minutes.
EXAMPLE XV
Radiodination of diatrizoic acid.
The following compounds were added together in the given sequence:
1) 0.6 mg of pure diatrizoic acid
2) 0.6 mg of citric acid
3) 280 .mu.l of oxygen-free water
4) 20 .mu.l of CuSO.sub.4 solution (32.5 mg CuSO.sub.4.5H.sub.2 O/10 ml)
5) radioiodide solution in amounts varying from 5 to 50 .mu.l.
The above mixture was heated at 100.degree. C. in a septum-closed vial
during 10-15 minutes. A labelling yield higher than 99% was obtained. No
labelled or unlabelled side-products could be detected.
By comparison diatrizoic acid was radiolabelled according to the method
described by Mills (Int. J. Appl. Rad. Isot., Vol 33, 1982, pp. 467-468).
0.16 mCi iodine-123 labelled sodiumiodide solution was added to 1 ml of a
solution containing 2.5 mg diatrizoic acid and 0.25 mg CuSO.sub.4.5H.sub.2
O per ml.
Prior to adding the radioiodide the pH of the solution was adjusted to 3.4
with 1N hydrochloric acid.
The mixture was heated for 15 minutes at 125.degree. C. After cooling to
room temperature 1.5 ml phosphate buffer (6.185 gram of dibasic
sodiumphosphate per 100 ml water) was added to adjust the pH to 7.0.
The solution was stirred for two minutes and passed through a 0.22 micron
filter.
The radiochemical purity was determined on HPLC using a Hewlett Packard RP8
10.mu. (dichrosorb) column and methanol/water/acetic acid 5/95/0.15 as the
mobile phase.
In four similar experiments an average yield of only 82% I-123 diatrizoic
acid was found.
EXAMPLE XVI
Presence of Sn (II) in the reaction mixture; influence of the presence of
higher oxidation states than I.sup.- on the reaction rate.
In addition Sn (II) can also achieve the reduction of entities with a
higher oxidation state than radioiodide, such as radioiodate, which can be
present in amounts up to more than 2-3% in commercially available
radioiodide solutions. It renders those species available as iodide for
the nucleophilic exchange reaction, e.g. the exchange of iodine by
radiolabelled iodine, thus allowing to obtain the high labelling yields
mentioned in the Examples before.
To determine the influence of Sn (II) on the radio-iodination when using
.sup.123- I-solutions of different qualities, the radioiodination was
carried out as described in Examples VIII to XII with radioiodide
solutions from various suppliers. It is well-known in the art, that the
labelling yields of earlier described methods are influenced by the
quality of the radioiodide solutions. It has now been found, however, that
in the above experiments the labelling yields did not differ
substantially.
EXAMPLE XVII
Equipment for preparing an injectable composition. The equipment is shown
in the Figure, wherein with reference numeral 1 a vial is denoted with an
internally conical bottom 2. The vial is sealingly closed with a stopper
3. Stopper 3 of vial 1 comprises a pierceable rubber disk 6, at the upper
side covered by an aluminium sheet 7 wherein two apertures 8 and 9 are
recessed. A screw cap 10 with a central aperture 11 keeps the rubber disk
6 and the aluminium sheet 7 tightly clamped on the upper edge of vial 1.
The reaction mixture, e.g. the kit preparation together with the
radioiodide solution, is accomodated in the vial and the reaction is
carried out by heating the reaction mixture at the desired temperature,
e.g. 100.degree. C. After the reaction is complete, the vial comprises a
solution of the product, e.g. the radioiodinated product, thus obtained.
In the Figure the supply syringe is denoted with reference numeral 4, the
injection syringe with 5. Both syringes are provided with hollow needles
12 and 13 respectively, which can be stuck through the apertures 8 and 9
in the aluminium sheet and through the rubber disk to allow communication
of the interior of the syringes with that of the vial. The syringes
further comprise cylindrical barrels 14 and 15 respectively, in which
plungers, 16 and 17 respectively, are movably positioned. Supply syringe 4
is intended for accomodating a formulation liquid, e.g. an isotonic
solution, and is provided with an aperture 18 in the side wall of its
barrel 14. The aperture 18 has such a distance from the needle mount, i.e.
the mounting means of the needle to the barrel, that in the original
position the plunger 16 separates the aperture 18 from the room 19 wherein
the formulation liquid is accomodated, whereas said room 19 can be allowed
to communicate with the atmospheric pressure outside the syringe via the
aperture by withdrawing plunger 16 up to above aperture 18. This latter
position of the plunger 16 is denoted in the Figure in dotted lines.
Injection syringe 5 can accomodate the injectable composition in room 21
and is provided with a sterilizing filter 22, e.g. of 0.22.mu., detachably
connected between injection needle 13 and the needle mount for mounting
the needle to barrel 15.
When the equipment shown in the Figure is used to prepare an injectable
composition, the stopper 3 of vial 1 is pierced (at 8) by needle 12 of
supply syringe 4. In the vial a solution of the product to be formulated
is accomodated. The supply syringe contains in room 19 a formulation
liquid, e.g. an isotonic solution. The supply syringe is then positioned
as shown in the Figure; the needle tip does not contact the solution in
the vial. In the same way the needle 13 of injection syringe 15 is stuck
through stopper 3 of vial 1 (at 9). The injection syringe is also
positioned as shown in the Figure; the needle extends into the solution to
the conical bottom of the vial so that the needle tip (nearly) contacts
this bottom. Injection syringe 15 is empty.
Thereupon plunger 16 of syringe 4 is withdrawn up to above aperture 18
(dotted lines), resulting in a communication between the formulation
liquid in this syringe with the atmospheric pressure. As a consequence of
this the formulation liquid flows through the hollow needle 12 into the
vial (see the arrow) and can easily be mixed with the contents of the vial
by shaking this vial.
The injectable composition thus obtained is then transferred from the vial
into the injection syringe 5 by withdrawing plunger 17 in the direction of
arrow 20. To collect a sterile composition in room 21 of barrel 15 of this
injection syringe, the composition reaches said room 21 via sterilizing
filter 22.
In a different embodiment of the present invention aperture 18 of supply
syringe 4 can be provided with a sterilizing filter. Then sterilizing
filter 22 may be omitted. This embodiment is preferably used when the
contents of vial 1 are already in a sterile condition.
Stabilizing filters may be omitted completely, when the equipment is
installed in a sterile room, e.g. in a laminar flow unit.
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